Digital Commons Network^™

Cooperative Activation Of Pdk1 And Akt By Mapk4 Enhances Cancer Growth And Resistance To Therapy, Dong Han, Wei Wang, Julie Heejin Jeon, Tao Shen, Xiangsheng Huang, Ping Yi, Bingning Dong, Feng Yang

Faculty, Staff and Students Publications

Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase of the protein A, G, and C (AGC) family kinases that play important roles in regulating cancer cell proliferation, survival, and metabolism. Besides phosphorylating/activating AKT at the cell membrane in a PI3K-dependent manner, PDK1 also exhibits constitutive activity on many other AGC kinases for tumor-promoting activity. In the latter case, PDK1 protein levels dominate its activity. We previously reported that MAPK4, an atypical MAPK, can PI3K-independently promote AKT activation and tumor growth. Here, using triple-negative breast cancer (TNBC) cell models, we demonstrate that MAPK4 can also enhance PDK1 protein synthesis, thus phosphorylate/activate PDK1 …

Delayed Skeletal Development And Igf-1 Deficiency In A Mouse Model Of Lysinuric Protein Intolerance, Bridget M Stroup, Xiaohui Li, Sara Ho, Haonan Zhouyao, Yuqing Chen, Safa Ani, Brian Dawson, Zixue Jin, Ronit Marom, Ming-Ming Jiang, Isabel Lorenzo, Daniel Rosen, Denise Lanza, Nathalie Aceves, Sara Koh, John R Seavitt, Jason D Heaney, Brendan Lee, Lindsay C Burrage

Faculty, Staff and Students Publications

SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6×129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective in this study was to characterize the skeletal phenotype in these mice. Compared to wild-type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations and delayed skeletal development. Because poor survival prevents …

Why Animal Experiments Are Still Indispensable In Bone Research: A Statement By The European Calcified Tissue Society, Merle Stein, Florent Elefteriou, Björn Busse, Imke Ak Fiedler, Ronald Young Kwon, Eric Farrell, Mubashir Ahmad, Anita Ignatius, Liam Grover, Liesbet Geris, Jan Tuckermann

Faculty, Staff and Students Publications

Major achievements in bone research have always relied on animal models and in vitro systems derived from patient and animal material. However, the use of animals in research has drawn intense ethical debate and the complete abolition of animal experimentation is demanded by fractions of the population. This phenomenon is enhanced by the reproducibility crisis in science and the advance of in vitro and in silico techniques. 3D culture, organ-on-a-chip, and computer models have improved enormously over the last years. Nevertheless, the overall complexity of bone tissue-cross talk and the systemic and local regulation of bone physiology can often only …

Prdm16 Deletion Is Associated With Sex-Dependent Cardiomyopathy And Cardiac Mortality: A Translational, Multi-Institutional Cohort Study, Ryan J Kramer, Amir Nima Fatahian, Alice Chan, Jeffery Mortenson, Jennifer Osher, Bo Sun, Lauren E Parker, Michael B Rosamilia, Kyra B Potter, Kaila Moore, Sage L Atkins, Jill A Rosenfeld, Alona Birjiniuk, Edward Jones, Taylor S Howard, Jeffrey J Kim, Daryl A Scott, Seema Lalani, Omid M T Rouzbehani, Samantha Kaplan, Marissa A Hathaway, Jennifer L Cohen, S Yukiko Asaki, Hugo R Martinez, Sihem Boudina, Andrew P Landstrom

Faculty, Staff and Students Publications

BACKGROUND: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor

METHODS: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific

RESULTS: The retrospective cohort included 71 patients. Among individuals with

CONCLUSIONS:

Shinybioheat: An Interactive Shiny App To Identify Phenotype Driver Genes In Ecoli And Bsubtilis, Chen Wang, Harikumar Govindarajan, Panagiotis Katsonis, Olivier Lichtarge

Faculty, Staff and Students Publications

SUMMARY: In any population under selective pressure, a central challenge is to distinguish the genes that drive adaptation from others which, subject to population variation, harbor many neutral mutations de novo. We recently showed that such genes could be identified by supplementing information on mutational frequency with an evolutionary analysis of the likely functional impact of coding variants. This approach improved the discovery of driver genes in both lab-evolved and environmental Escherichia coli strains. To facilitate general adoption, we now developed ShinyBioHEAT, an R Shiny web-based application that enables identification of phenotype driving gene in two commonly used model bacteria, …

The Clinical And Genetic Spectrum Of Autosomal-Recessive Tor1a-Related Disorders, Afshin Saffari, Tracy Lau, Homa Tajsharghi, Ehsan Ghayoor Karimiani, Ariana Kariminejad, Stephanie Efthymiou, Giovanni Zifarelli, Tipu Sultan, Mehran Beiraghi Toosi, Sahar Sedighzadeh, Victoria Mok Siu, Juan Darío Ortigoza-Escobar, Aisha M Alshamsi, Shahnaz Ibrahim, Nouriya Abbas Al-Sannaa, Walla Al-Hertani, Whalen Sandra, Mark Tarnopolsky, Shahryar Alavi, Chumei Li, Debra-Lynn Day-Salvatore, Maria Jesús Martínez-González, Kristin M Levandoski, Emma Bedoukian, Suneeta Madan-Khetarpal, Michaela J Idleburg, Minal Juliet Menezes, Aishwarya Siddharth, Konrad Platzer, Henry Oppermann, Martin Smitka, Felicity Collins, Monkol Lek, Mohmmad Shahrooei, Maryam Ghavideldarestani, Isabella Herman, John Rendu, Julien Faure, Janice Baker, Vikas Bhambhani, Laurel Calderwood, Javad Akhondian, Shima Imannezhad, Hanieh Sadat Mirzadeh, Narges Hashemi, Mohammad Doosti, Mojtaba Safi, Najmeh Ahangari, Paria Najarzadeh Torbati, Soheila Abedini, Vincenzo Salpietro, Elif Yilmaz Gulec, Safieh Eshaghian, Mohammadreza Ghazavi, Michael T Pascher, Marina Vogel, Angela Abicht, Sébastien Moutton, Ange-Line Bruel, Claudine Rieubland, Sabina Gallati, Tim M Strom, Hanns Lochmüller, Mohammad Hasan Mohammadi, Javeria Raza Alvi, Elaine H Zackai, Beth A Keena, Cara M Skraban, Seth I Berger, Erin H Andrew, Elham Rahimian, Michelle M Morrow, Ingrid M Wentzensen, Francisca Millan, Lindsay B Henderson, Hormos Salimi Dafsari, Heinz Jungbluth, Natalia Gomez-Ospina, Anne Mcrae, Merlene Peter, Danai Veltra, Nikolaos M Marinakis, Christalena Sofocleous, Farah Ashrafzadeh, Davut Pehlivan, Johannes R Lemke, Judith Melki, Audrey Benezit, Peter Bauer, Denisa Weis, James R Lupski, Jan Senderek, John Christodoulou, Wendy K Chung, Rose Goodchild, Amaka C Offiah, Andres Moreno-De-Luca, Mohnish Suri, Darius Ebrahimi-Fakhari, Henry Houlden, Reza Maroofian

Faculty, Staff and Students Publications

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of …

Clinical And Functional Heterogeneity Associated With The Disruption Of Retinoic Acid Receptor Beta, Véronique Caron, Nicolas Chassaing, Nicola Ragge, Felix Boschann, Angelina My-Hoa Ngu, Elisabeth Meloche, Sarah Chorfi, Saquib A Lakhani, Weizhen Ji, Laurie Steiner, Julien Marcadier, Philip R Jansen, Laura A Van De Pol, Johanna M Van Hagen, Alvaro Serrano Russi, Gwenaël Le Guyader, Magnus Nordenskjöld, Ann Nordgren, Britt-Marie Anderlid, Julie Plaisancié, Corinna Stoltenburg, Denise Horn, Anne Drenckhahn, Fadi F Hamdan, Mathilde Lefebvre, Tania Attie-Bitach, Peggy Forey, Vasily Smirnov, Françoise Ernould, Marie-Line Jacquemont, Sarah Grotto, Alberto Alcantud, Alicia Coret, Rosario Ferrer-Avargues, Siddharth Srivastava, Catherine Vincent-Delorme, Shelby Romoser, Nicole Safina, Dimah Saade, James R Lupski, Daniel G Calame, David Geneviève, Nicolas Chatron, Caroline Schluth-Bolard, Kenneth A Myers, William B Dobyns, Patrick Calvas, Ddd Study, Caroline Salmon, Richard Holt, Frances Elmslie, Marc Allaire, Daniil M Prigozhin, André Tremblay, Jacques L Michaud

Faculty, Staff and Students Publications

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.

METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.

RESULTS: We found that …

Broadening The Phenotypic And Molecular Spectrum Of Finca Syndrome: Biallelic Nhlrc2 Variants In 15 Novel Individuals, Henrike L Sczakiel, Max Zhao, Brigitte Wollert-Wulf, Magdalena Danyel, Nadja Ehmke, Corinna Stoltenburg, Nadirah Damseh, Motee Al-Ashhab, Tugce B Balci, Matthew Osmond, Andrea Andrade, Jens Schallner, Joseph Porrmann, Kimberly Mcdonald, Mingjuan Liao, Henry Oppermann, Konrad Platzer, Nadine Dierksen, Majid Mojarrad, Atieh Eslahi, Behnaz Bakaeean, Daniel G Calame, James R Lupski, Zahra Firoozfar, Seyed Mohammad Seyedhassani, Seyed Ahmad Mohammadi, Najwa Anwaar, Fatima Rahman, Dominik Seelow, Martin Janz, Denise Horn, Reza Maroofian, Felix Boschann

Faculty, Staff and Students Publications

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.

Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with …

Dental Pulp Stem Cells And Current In Vivo Approaches To Study Dental Pulp Stem Cells In Pulp Injury And Regeneration, Dongwook Yang, Jea Giezl Niedo Solidum, Dongsu Park

Faculty, Staff and Students Publications

Dental pulp stem cells (DPSCs) have garnered significant interest in dental research for their unique characteristics and potential in tooth development and regeneration. While there were many studies to define their stem cell-like characteristics and osteogenic differentiation functions that are considered ideal candidates for regenerating damaged dental pulp tissue, how endogenous DPSCs respond to dental pulp injury and supply new dentin-forming cells has not been extensively investigated in vivo. Here, we review the recent progress in identity, function, and regulation of endogenous DPSCs and their clinical potential for pulp injury and regeneration. In addition, we discuss current advances in new …

Multiscale Analysis Of Pangenomes Enables Improved Representation Of Genomic Diversity For Repetitive And Clinically Relevant Genes, Chen-Shan Chin, Sairam Behera, Asif Khalak, Fritz J Sedlazeck, Peter H Sudmant, Justin Wagner, Justin M Zook

Faculty, Staff and Students Publications

Advancements in sequencing technologies and assembly methods enable the regular production of high-quality genome assemblies characterizing complex regions. However, challenges remain in efficiently interpreting variation at various scales, from smaller tandem repeats to megabase rearrangements, across many human genomes. We present a PanGenome Research Tool Kit (PGR-TK) enabling analyses of complex pangenome structural and haplotype variation at multiple scales. We apply the graph decomposition methods in PGR-TK to the class II major histocompatibility complex demonstrating the importance of the human pangenome for analyzing complicated regions. Moreover, we investigate the Y-chromosome genes, DAZ1/DAZ2/DAZ3/DAZ4, of which structural variants have been linked to …

Proteomics Of Adjacent-To-Tumor Samples Uncovers Clinically Relevant Biological Events In Hepatocellular Carcinoma, Hongwen Zhu, Youpei Lin, Dayun Lu, Shisheng Wang, Yuejia Liu, Liangqing Dong, Qian Meng, Jing Gao, Yuqiu Wang, Nixue Song, Yuying Suo, Li Ding, Pei Wang, Bing Zhang, Daming Gao, Jia Fan, Qiang Gao, Hu Zhou

Faculty, Staff and Students Publications

Normal adjacent tissues (NATs) of hepatocellular carcinoma (HCC) differ from healthy liver tissues and their heterogeneity may contain biological information associated with disease occurrence and clinical outcome that has yet to be fully evaluated at the proteomic level. This study provides a detailed description of the heterogeneity of NATs and the differences between NATs and healthy livers and revealed that molecular features of tumor subgroups in HCC were partially reflected in their respective NATs. Proteomic data classified HCC NATs into two subtypes (Subtypes 1 and 2), and Subtype 2 was associated with poor prognosis and high-risk recurrence. The pathway and …

Isolation And Characterization Of Porcine Endocardial Endothelial Cells, Kathleen N Brown, Hong Kim T Phan, Elysa L Jui, Marci K Kang, Jennifer P Connell, Sundeep G Keswani, K Jane Grande-Allen

Faculty, Staff and Students Publications

The heart contains diverse endothelial cell types. We sought to characterize the endocardial endothelial cells (EECs), which line the chambers of the heart. EECs are relatively understudied, yet their dysregulation can lead to various cardiac pathologies. Due to the lack of commercial availability of these cells, we reported our protocol for isolating EECs from porcine hearts and for establishing an EEC population through cell sorting. In addition, we compared the EEC phenotype and fundamental behaviors to a well-studied endothelial cell line, human umbilical vein endothelial cells (HUVECs). The EECs stained positively for classic phenotypic markers such as CD31, von Willebrand …

Effects Of Cathepsin S Inhibition In The Age-Related Dry Eye Phenotype, Jeremias G Galletti, Kaitlin K Scholand, Claudia M Trujillo-Vargas, Wolfgang Haap, Tiago Santos-Ferreira, Christoph Ullmer, Zhiyuan Yu, Cintia S De Paiva

Faculty, Staff and Students Publications

PURPOSE: Aged C57BL/6J (B6) mice have increased levels of cathepsin S, and aged cathepsin S (Ctss-/-) knockout mice are resistant to age-related dry eye. This study investigated the effects of cathepsin S inhibition on age-related dry eye disease.

METHODS: Female B6 mice aged 15.5 to 17 months were randomized to receive a medicated diet formulated by mixing the RO5461111 cathepsin S inhibitor or a standard diet for at least 12 weeks. Cornea mechanosensitivity was measured with a Cochet-Bonnet esthesiometer. Ocular draining lymph nodes and lacrimal glands (LGs) were excised and prepared for histology or assayed by flow cytometry to quantify …

Machine Learning Driven Index Of Tumor Multinucleation Correlates With Survival And Suppressed Anti-Tumor Immunity In Head And Neck Squamous Cell Carcinoma Patients, Can F Koyuncu, Mitchell J Frederick, Lester D R Thompson, Germán Corredor, Sirvan Khalighi, Zelin Zhang, Bolin Song, Cheng Lu, Reetoja Nag, Vidya Sankar Viswanathan, Michael Gilkey, Kailin Yang, Shlomo A Koyfman, Deborah J Chute, Patricia Castro, James S Lewis, Anant Madabhushi, Vlad C Sandulache

Faculty, Staff and Students Publications

OBJECTIVES: Matching treatment intensity to tumor biology is critical to precision oncology for head and neck squamous cell carcinoma (HNSCC) patients. We sought to identify biological features of tumor cell multinucleation, previously shown by us to correlate with survival in oropharyngeal (OP) SCC using a machine learning approach.

MATERIALS AND METHODS: Hematoxylin and eosin images from an institutional OPSCC cohort formed the training set (D

RESULTS: MuNI correlated with overall survival. A multivariable nomogram that included MuNI, age, race, sex, T/N stage, and smoking status yielded a C-index of 0.65, and MuNI was prognostic of overall survival (2.25, 1.07-4.71, 0.03), …

Deployment Of Cisplatin In Veterans With Oropharyngeal Cancer: Toxicity And Impact On Oncologic Outcomes, Ola Soliman, David C Wilde, Jan O Kemnade, Anita L Sabichi, George Chen, Albert Chen, Samantha N Little, Andrew T Huang, David J Hernandez, Vlad C Sandulache

Faculty, Staff and Students Publications

OBJECTIVE: Cisplatin forms the backbone of systemic chemotherapy treatment for oropharyngeal squamous cell carcinoma (OPSCC). The ideal cisplatin dosing regimen remains yet to be fully defined for achieving optimal efficacy and toxicity profiles in patients with comorbidity.

METHODS: We retrospectively reviewed oncologic and toxicity data for patients with OPSCC treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2000 and 2020 who initiated curative intent, definitive chemo-radiation with one of three single agent regimens: high dose (HD) cisplatin, low dose (LD) cisplatin or cetuximab.

RESULTS: Patients with HPV-associated tumors and nonsmokers demonstrated improved overall and disease-free survival along …

Androgen-Regulated Stromal Complement Component 7 (C7) Suppresses Prostate Cancer Growth, Zhicheng Zhou, Deyong Jia, Ohjoon Kwon, Shan Li, Huiyun Sun, Martine P Roudier, Daniel W Lin, Lawrence True, Colm Morrissey, Chad J Creighton, John K Lee, Li Xin

Faculty, Staff and Students Publications

The complement system is a major component of the innate immune system that works through the cytolytic effect of the membrane attack complex (MAC). Complement component 7 (C7) is essential for MAC assembly and its precisely regulated expression level is crucial for the cytolytic activity of MAC. We show that C7 is specifically expressed by the stromal cells in both mouse and human prostates. The expression level of C7 inversely correlates with clinical outcomes in prostate cancer. C7 is positively regulated by androgen signaling in the mouse prostate stromal cells. The androgen receptor directly transcriptionally regulates the mouse and human …

Variation In Early Anakinra Use And Short-Term Outcomes In Multisystem Inflammatory Syndrome In Children, Joyce C Chang, Cameron C Young, Eyal Muscal, Sara K Sexson Tejtel, Margaret M Newhams, Suden Kucukak, Hillary Crandall, Aline B Maddux, Courtney M Rowan, Natasha B Halasa, Helen A Harvey, Charlotte V Hobbs, Mark W Hall, Michele Kong, Cassyanne L Aguiar, Jennifer E Schuster, Julie C Fitzgerald, Aalok R Singh, Kari Wellnitz, Ryan A Nofziger, Natalie Z Cvijanovich, Elizabeth H Mack, Adam J Schwarz, Sabrina M Heidemann, Jane W Newburger, Laura D Zambrano, Angela P Campbell, Manish M Patel, Adrienne G Randolph, Mary Beth F Son, Overcoming Covid Investigators

Faculty, Staff and Students Publications

OBJECTIVE: Evidence regarding effectiveness of interleukin-1 receptor antagonism in multisystem inflammatory syndrome in children (MIS-C) is lacking. We characterized variation in initial treatment with anakinra and evaluated cardiovascular outcomes associated with adding anakinra to standard initial therapy.

METHODS: We conducted a retrospective cohort study of MIS-C cases in a US surveillance registry from November 2020 to December 2021. Day 0 was the first calendar day of immunomodulatory treatment. Factors associated with initial anakinra use (days 0-1) were identified. We compared cases in patients ages 2-20 years receiving intravenous immunoglobulin (IVIG) and glucocorticoids versus anakinra plus IVIG and/or glucocorticoids on days …

The Sunbeam Birth Cohort: Protocol Design, Corinne Keet, Scott H Sicherer, Supinda Bunyavanich, Cynthia Visness, Patricia C Fulkerson, Alkis Togias, Wendy Davidson, Susan Perry, Sanaz Hamrah, Agustin Calatroni, Katina Robinson, Lars Dunaway, Carla M Davis, Sara Anvari, Susan M Leong-Kee, Gurjit Khurana Hershey, Emily Defranco, Ashley Devonshire, Haejin Kim, Christine Joseph, Brent Davidson, Noel K Strong, Angela J Tsuang, Marion Groetch, Julie Wang, Jennifer Dantzer, Kim Mudd, Abimbola Aina, Wayne Shreffler, Qian Yuan, Virginia Simmons, Donald Y M Leung, Jessica Hui-Beckman, Jania Arcia Ramos, Sharon Chinthrajah, Virginia Winn, Tina Sindher, Stacie M Jones, Nirvana A Manning, Amy M Scurlock, Edwin Kim, Alison Stuebe, James E Gern, Anne Marie Singh, Jennifer Krupp, Robert A Wood

Faculty, Staff and Students Publications

BACKGROUND: Food allergy (FA) and atopic dermatitis (AD) are common conditions that often present in the first year of life. Identification of underlying mechanisms and environmental determinants of FA and AD is essential to develop and implement effective prevention and treatment strategies. Objectives: We sought to describe the design of the Systems Biology of Early Atopy (SunBEAm) birth cohort.

METHODS: Funded by the National Institute of Allergy and Infectious Diseases (NIAID) and administered through the Consortium for Food Allergy Research (CoFAR), SunBEAm is a US population-based, multicenter birth cohort that enrolls pregnant mothers, fathers, and their newborns and follows them …

T-Cell Receptor Beta Variable Gene Polymorphism Predicts Immune-Related Adverse Events During Checkpoint Blockade Immunotherapy, Bettzy Stephen, Joud Hajjar, Shrutii Sarda, Dzifa Yawa Duose, Jeffrey M Conroy, Carl Morrison, Anas Alshawa, Mingxuan Xu, Abdulrazzak Zarifa, Sapna P Patel, Ying Yuan, Evan Kwiatkowski, Linghua Wang, Jordi Rodon Ahnert, Siqing Fu, Funda Meric-Bernstam, Geoffrey M Lowman, Timothy Looney, Aung Naing

Faculty, Staff and Students Publications

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the …

Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma: Pathogenesis And Treatment, Josep M Llovet, Catherine E Willoughby, Amit G Singal, Tim F Greten, Mathias Heikenwälder, Hashem B El-Serag, Richard S Finn, Scott L Friedman

Faculty, Staff and Students Publications

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation, nonalcoholic steatohepatitis (NASH), has a global prevalence of 20-25% and is a major public health problem. Its incidence is increasing in parallel to the rise in obesity, diabetes and metabolic syndrome. Progression from NASH to NASH-related hepatocellular carcinoma (HCC) (~2% of cases per year) is influenced by many factors, including the tissue and immune microenvironment, germline mutations in PNPLA3, and the microbiome. NASH-HCC has unique molecular and immune traits compared with other aetiologies of HCC and is equally prevalent in men and women. Comorbidities associated with NASH, such as obesity …

Noncanonical Binding Of Transcription Factors: Time To Revisit Specificity?, Md Abul Hassan Samee

Faculty, Staff and Students Publications

Transcription factors (TFs) are one of the most studied classes of DNA-binding proteins that have a direct functional impact on gene transcription and thus, on human physiology and disease. The mechanisms that TFs use for recognizing target DNA binding sites have been studied for nearly five decades, yet they remain poorly understood. It is classically assumed that a TF recognizes a specific sequence pattern, or motif, as its binding sites. However, recent studies are consistently finding examples of noncanonical binding, that is, TFs binding at sites that do not resemble their sequence motifs. Here we review the current literature on …

Crat Links Cholesterol Metabolism To Innate Immune Responses In The Heart, Hua Mao, Aude Angelini, Shengyu Li, Guangyu Wang, Luge Li, Cam Patterson, Xinchun Pi, Liang Xie

Faculty, Staff and Students Publications

Chronic inflammation is associated with increased risk and poor prognosis of heart failure; however, the precise mechanism that provokes sustained inflammation in the failing heart remains elusive. Here we report that depletion of carnitine acetyltransferase (CRAT) promotes cholesterol catabolism through bile acid synthesis pathway in cardiomyocytes. Intracellular accumulation of bile acid or intermediate, 7α-hydroxyl-3-oxo-4-cholestenoic acid, induces mitochondrial DNA stress and triggers cGAS-STING-dependent type I interferon responses. Furthermore, type I interferon responses elicited by CRAT deficiency substantially increase AIM2 expression and AIM2-dependent inflammasome activation. Genetic deletion of cardiomyocyte CRAT in mice of both sexes results in myocardial inflammation and dilated cardiomyopathy, …

Kinase Inhibitor Pulldown Assay Identifies A Chemotherapy Response Signature In Triple-Negative Breast Cancer Based On Purine-Binding Proteins, Junkai Wang, Alexander B Saltzman, Eric J Jaehnig, Jonathan T Lei, Anna Malovannaya, Matthew V Holt, Meggie N Young, Mothaffar F Rimawi, Foluso O Ademuyiwa, Meenakshi Anurag, Beom-Jun Kim, Matthew J Ellis

Faculty, Staff and Students Publications

Triple-negative breast cancer (TNBC) constitutes 10%–15% of all breast tumors. The current standard of care is multiagent chemotherapy, which is effective in only a subset of patients. The original objective of this study was to deploy a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) to identify kinases elevated in non-pCR (pathologic complete response) cases for therapeutic targeting. Frozen optimal cutting temperature compound–embedded core needle biopsies were obtained from 43 patients with TNBC before docetaxel- and carboplatin-based neoadjuvant chemotherapy. KIPA was applied to the native tumor lysates that were extracted from samples with high tumor content. Seven percent of all …

Combining Voltage-Sensitive Dye, Carbon Fiber Array, And Extracellular Nerve Electrodes Using A 3-D Printed Recording Chamber And Manipulators, Curtis L Neveu, Yu Huan, Yuto Momohara, Paras R Patel, Hillel J Chiel, Cynthia A Chestek, John H Byrne

Faculty, Staff and Student Publications

BACKGROUND: The analyses of neuronal circuits require high-throughput technologies for stimulating and recording many neurons simultaneously with single-neuron precision. Voltage-sensitive dyes (VSDs) have enabled the monitoring of membrane potentials of many (10-100 s) neurons simultaneously. Carbon fiber electrode (CFE) arrays allow for stimulation and recording of many neurons simultaneously, including intracellularly.

NEW METHOD: Combining CFE with VSD leverages the advantages of both technologies, allowing for stimulation of single neurons while recording the activity of the entire network. 3-D printing technology was used to develop a chamber to simultaneously perform VSD imaging, CFE array recording, and extracellular recording from individual glass …

Spatial Analyses Of Immune Cell Infiltration In Cancer: Current Methods And Future Directions: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, David B Page, Glenn Broeckx, Chowdhury Arif Jahangir, Sara Verbandt, Rajarsi R Gupta, Jeppe Thagaard, Reena Khiroya, Zuzana Kos, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Sarah N Dudgeon, Mahmoud Elghazawy, Scott Ely, Claudio Fernandez-Martín, Susan Fineberg, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Alexandros Hardas, Steven N Hart, Johan Hartman, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Sylvia Adams, John Mark Seaverns Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical …

Pitfalls In Machine Learning-Based Assessment Of Tumor-Infiltrating Lymphocytes In Breast Cancer: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, Jeppe Thagaard, Glenn Broeckx, David B Page, Chowdhury Arif Jahangir, Sara Verbandt, Zuzana Kos, Rajarsi Gupta, Reena Khiroya, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Mohamed Amgad, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Eva Balslev, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Alexandros Chardas, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Anders B Dahl, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Johan Doré Hansen, Sarah N Dudgeon, Thomas Ebstrup, Mahmoud Elghazawy, Claudio Fernandez-Martín, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Steven N Hart, Johan Hartman, Søren Hauberg, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Roslind, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Ely Scott, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Susan Fineberg, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Reena Md Zin, Sylvia Adams, John Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. …

Mitotic Rate In Primary Cutaneous Melanoma: Cell Division Matters, Jeffrey E Gershenwald

Faculty, Staff and Student Publications

No abstract provided.

Predictive Model Of Liver Toxicity To Aid The Personalized Selection Of Proton Versus Photon Therapy In Hepatocellular Carcinoma, Ibrahim Chamseddine, Yejin Kim, Brian De, Issam El Naqa, Dan G Duda, John A Wolfgang, Jennifer Pursley, Jennifer Y Wo, Theodore S Hong, Harald Paganetti, Eugene J Koay, Clemens Grassberger

Faculty, Staff and Student Publications

Purpose: Our objective was to develop an externally validated model for predicting liver toxicity after radiation therapy in patients with hepatocellular carcinoma (HCC) that can integrate both photon and proton dose distributions with patient-specific characteristics.

Methods and materials: Training data consisted of all patients with HCC treated between 2008 and 2019 at our institution (n = 117, 60%/40% photon/proton). We developed a shallow convolutional neural network (CNN) to predict posttreatment liver dysfunction from the differential dose-volume histogram (DVH) and baseline liver metrics. To reduce bias and improve robustness, we used ensemble learning (CNNE). After a preregistered study analysis plan, we …

Ultrasensitive Ngs Mrd Assessment In Ph+ All: Prognostic Impact And Correlation With Rt-Pcr For Bcr::Abl1, Nicholas J Short, Elias Jabbour, Walid Macaron, Farhad Ravandi, Nitin Jain, Rashmi Kanagal-Shamanna, Keyur P Patel, Sanam Loghavi, Fadi G Haddad, Musa Yilmaz, Ghayas C Issa, Partow Kebriaei, Steven M Kornblau, Sarah Pelletier, Wilmer Flores, Jairo Matthews, Rebecca Garris, Hagop Kantarjian

Faculty, Staff and Student Publications

Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, RT-PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay (sensitivity of 10-6 ) and its correlation with RT-PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT-PCR and NGS, and 31% of patients who achieved NGS MRD negativity were …

Biological Effects Of New Titanium Surface Coatings Based On Ionic Liquids And Hmgb1: A Cellular And Molecular Characterization In Lewis Rats, Alexandra Arteaga, Cláudia Cristina Biguetti, Bhuvana Lakkasetter Chandrashekar, Jimena Mora, Adeena Qureshi, Danieli C. Rodrigues

School of Podiatric Medicine Publications

High Mobility Group Box 1 (HMGB1) is a redox-sensitive molecule that plays dual roles in tissue healing and inflammation. We previously demonstrated that HMGB1 is stable when anchored by a well-characterized imidazolium-based ionic liquid (IonL), which serves as a delivery vehicle for exogenous HMGB1 to the site of injury and prevents denaturation from surface adherence. However, HMGB1 exists in different isoforms [fully reduced HMGB1 (FR), a recombinant version of FR resistant to oxidation (3S), disulfide HMGB1 (DS), and inactive sulfonyl HMGB1(SO)] that have distinct biological functions in health and disease. Thus, the goal of this study was to evaluate the …